In this era of molecular oncology, several markers in glioblastoma have proven to be prognostic. Of them, O 6-methylguanin-DNA-methyltransferase (MGMT) promoter methylation has undoubtedly stolen the lime light. Ever since the seminal discovery that MGMT promoter methylation confers better prognosis by interfering with the DNA repair in response to temozolamide induced damage,[1],[2] the management of glioblastoma had two major inclusions, i.e., the addition of concomitant and cyclical temozolamide to radiation therapy, and the evaluation MGMT promoter methylation status to infer the prognosis. Several groups have studied the significance of this marker in glioblastoma and the possibility of personalizing the treatment based on this marker. While some groups have found that the marker is predictive and prognostic,[3],[4] some others have found that it is prognostic but not predictive.[5] Though the prognostic significance of MGMT is uncontested, as seen in the NORDIC trial,[6] its role in personalized medicine proved to be worthwhile in elderly patients with a glioblastoma, as observed by the Neurooncology Working group of the German Cancer Society in the NOA-08 trial.[7] While the NOA-08 trial showed that temozolamide alone treatment was not inferior to radiation treatment alone in elderly patients with methylated MGMT promoter, newer trials have shown that a short course radiation therapy in combination with temozolamide was the recommended treatment regimen in elderly patients with a glioblastoma who are eligible for the combination therapy.[8] However, in MGMT methylated elderly patients who are not eligible for radiation therapy, temozolamide alone may be a convenient pragmatic option. Thus stands the role of MGMT in personalized medicine in glioblastoma.

Another major nuance introduced in glioblastoma research after the discovery of MGMT promoter methylation, is the inclusion of MGMT promoter methylation status as one of the stratifying factors in clinical trials, for example, the NCT01280552, NCT02287428, VERTU, ACTR-50(VAL-083) and other clinical trials. However, several of the trials showing MGMT promoter methylation as a positive prognostic factor, had a bias of low incidence of early deaths due to the selection criteria.[9] Also, the results of the trials report the outcomes in only those patients who survived long enough to complete the allotted regimen. Moreover, the trials assessing MGMT promoter methylation have conclusively proven its prognostic significance with respect to the overall survival but some of them have questioned its significance in progression free survival,[10] thus preventing the scientific community from coming to a conclusion regarding personalizing treatment based on MGMT promoter methylation.

Parallel to the clinical trials, studies have investigated various methods to evaluate the MGMT promoter methylation status in diagnostic neuropathology laboratories. Several studies have investigated the utility of methylation-specific multiplex ligation-dependent probe amplification (MS- MLPA), methylation specific polymerase chain reaction (MSP) and pyrosequencing in determining MGMT status. To sum up those studies, MGMT methylation is best identified when the two out of these three methods are utilised in conjunction to study the same.[11] However, MSP is a cost effective method and widely used in a resource limited setting. The correlation of other prognostic markers in glioblastoma, with MGMT promoter methylation status, has been elusive despite several studies.

This commentary reviews the work of Arora et al.,[12] who have studied the MGMT promoter methylation in 134 glioblastoma patients and correlated this with other prognostic markers, namely isocitrate dehydrogenase (IDH) mutation, adenosine triphosphate-dependent helicase transcriptional regular-X linked (ATRX) mutation and epidermal growth factor receptor (EGFR) amplification. Importantly, the authors have included patients with a short survival and studied their molecular characteristics. They have investigated MGMT promoter methylation status using methylation specific polymerase chain reaction (PCR) technique which gave unequivocal results in a majority of the cases. However, the results were inconclusive in 14 cases. This further adds to the growing mound of literature which questions the appropriate testing method for MGMT and the need to standardize a method if it were to see the light of personalized medicine. The authors have shown that MGMT promoter methylation correlates with IDH and ATRX mutation, which is a well-known observation.

Although the authors were not able to demonstrate the prognostic significance of MGMT promoter methylation by itself in their cohort, of note is their finding that confluent necrosis turned out to be a statistically significant predictor of MGMT promoter methylation status, where presence of confluent necrosis predicts an unmethylated MGMT promoter. Also, their study shows that the majority of the MGMT promoter methylated glioblastoma tumors were located in the frontal lobe. These subtle indicators become important in the present scenario where MSP alone might generate inconclusive results. In face of an inconclusive test, the pathologist should be able to take the help of subtle indicators in reaching a conclusion. Though statistical analysis for survival was not performed in view of the short duration of follow-up, they have observed that among the 16 patients who succumbed to the disease, 10 had a methylated MGMT promoter and 6 had an unmethylated MGMT promoter. This observation sets off a rhetoric as to the prognostic and predictive value of the marker in short-term survivors.[12]

MGMT promoter methylation, although well established, remains the grey area of glioblastoma research, especially in a resource limited setting like India where the recommended Stupp's regimen cannot be received by all patients, the cost of treatment being one of the major causes for defaulting. Incomplete and non-uniform treatment prevents the scientific bodies from including the short-term survivors in the analysis. This becomes a limiting factor in studying glioblastoma in its entirety. These clinically relevant hurdles need to be overcome in order to be able to evaluate the true significance of MGMT promoter methylation in all glioblastoma patients, short-term survivors and otherwise.